Insights into pathological mechanisms and interventions revealed by analyzing a mathematical model for cone metabolism

Journal Article · 08 March 2022 · Bioscience Reports

DOI: https://doi.org/10.1042/bsr20212457 · OSTI ID:1863736

Dobreva, Atanaska  ^[1]; Camacho, Erika Tatiana ^[1]; Larripa, Kamila ^[2]; Rǎdulescu, Anca ^[3]; Schmidt, Deena R ^[4]; Trejo, Imelda  ^[5]

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1. Arizona State Univ., Glendale, AZ (United States)
2. Humboldt State Univ., Arcata, CA (United States)
3. State Univ. of New York (SUNY), New Paltz, NY (United States)
4. Univ. of Nevada, Reno, NV (United States)
5. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

This work analyzes a mathematical model for the metabolic dynamics of a cone photoreceptor, which is the first model to account for energy generation from fatty acids oxidation of shed photoreceptor outer segments (POS). Multiple parameter bifurcation analysis shows that joint variations in external glucose, the efficiency of glucose transporter 1 (GLUT1), lipid utilization for POS renewal, and oxidation of fatty acids affect the cone’s metabolic vitality and its capability to adapt under glucose-deficient conditions. The analysis further reveals that when glucose is scarce, cone viability cannot be sustained by only fueling energy production in the mitochondria, but it also requires supporting anabolic processes to create lipids necessary for cell maintenance and repair. In silico experiments are used to investigate how the duration of glucose deprivation impacts the cell without and with a potential GLUT1 or oxidation of fatty acids intervention as well as a dual intervention. The results show that for prolonged duration of glucose deprivation, the cone metabolic system does not recover with higher oxidation of fatty acids and requires greater effectiveness of GLUT1 to recover. Finally, time-varying global sensitivity analysis (GSA) is applied to assess the sensitivity of the model outputs of interest to changes and uncertainty in the parameters at specific times. The results reveal a critical temporal window where there would be more flexibility for interventions to rescue a cone cell from the detrimental consequences of glucose shortage.

• Research Organization: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
• Sponsoring Organization: USDOE
• Grant/Contract Number: 89233218CNA000001
• OSTI ID: 1863736
• Report Number(s): LA-UR-21-23120
• Journal Information: Bioscience Reports, Journal Name: Bioscience Reports Journal Issue: 3 Vol. 42; ISSN 0144-8463
• Publisher: Portland Press - Biochemical SocietyCopyright Statement
• Country of Publication: United States
• Language: English